Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

doi:10.1074/jbc.M611599200

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines*

Departments of ^‡Biochemistry and ^**Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, ^§Center for Neurosciences and Aging and ^¶Cancer Center, The Burnham Institute for Medical Research, La Jolla, California 92037, and ^∥Raylight Corporation, Chemokine Pharmaceutical Inc., La Jolla, California 92037

1 To whom correspondence should be addressed: The Burnham Inst. for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-9928; E-mail: ziweihuang{at}burnham.org.

Abstract

As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1α or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1α or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120_IIIB, and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

Footnotes

↵2 The abbreviations used are: HAD, HIV-associated dementia; HIV-1, human immunodeficiency virus type 1; MAPK, mitogen-activated protein kinase; SMM, synthetically and modularly modified; vMIP-II, viral macrophage inflammatory protein-II; SDF-1α, stromal cell-derived factor-1α; RCCs, rodent cerebrocortical cultures; wt, wild type; TFA, trifluoroacetic acid; RP-HPLC, reverse phase-high performance liquid chromatography; ERK, extracellular regulated kinase; JNK, c-JUN N-terminal kinase; PBS, phosphate-buffered saline; MIP-1β, macrophage inflammatory protein-1β.
↵3 M. Kaul, K. E. Medders, M. K. Desai, and S. A. Lipton, unpublished data.
↵* This work was supported in part by National Institutes of Health Grants R01 GM5776105 (to Z. H.), R01 NS050621 (to M. K.), and P01 HD29587, R01 EY09024, and R01 NS41207 (to S. A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received December 19, 2006.
The American Society for Biochemistry and Molecular Biology, Inc.